The overall objective of this project is to design and prepare compounds which are selective for one of the forms of cyclic nucleotide phosphodiesterase, and to examine the possibility of obtaining tissue selective agents based on the relative distribution of the two or more forms of cyclic nucleotide phosphodiesterases in various tissues. We will design and prepare compounds in the xanthine series in order to attempt to increase the specificity of the parent compound (1-methyl-3-isobutylxanthine) for inhibition of one of the two forms of cyclic nucleotide phosphodiesterase from pig coronary artery. We have prepared compounds which are 40-50 fold more potent as inhibitors of peak I (low Km cyclic GMP phosphodiesterase) than of peak II (low Km cyclic AMP phosphodiesterase). We will, in the coming year, attempt to prepare compounds which are selective for inhibition of peak II phosphodiesterase and study the effect of these agents on the separated enzymes from other tissues. BIBLIOGRAPHIC REFERENCES: The following manuscripts were published during the period indicated. J.N. Wells, Y.J. Wu, C.E. Baird and J.G. Hardman, Phosphodiesterases from porcine coronary arteries: inhibition of separated forms by xanthines, papaverine and cyclic nucleotides, Mol. Pharmacol. II, 775-783 (1975). J.E. Garst, G.L. Kramer, Y.J. Wu and J.N. Wells, Inhibition of separated forms of phosphodiesterases from pig coronary arteries by uracils and by 7-substituted derivatives of 1-methyl-3-isobutylxanthine, J. Med. Chem. (in press, April, 1976).